Approximately 0.1% of adults in the USA are hospitalized each year for urinary calculi (e.g. kidney stones), of which about 80% are primarily calcium oxalate. Patients at risk for urinary calculi generally include those with calculi or who have had calculi in the past, those with renal insufficiency, those on diets containing a large amount of oxalate, those with ileal disease, ileal resection, or jejeunoileal bypass, those with chronic biliary or pancreatic disease, and those with a family history of calculi. Thus, there is a need for superior oxalate reducers.
The invention relates to the discovery that a class of polymers have improved oxalate binding properties. The polymers employed in the invention comprise water-insoluble, non-absorbable, and optionally cross-linked polyamines as defined herein. The polyamines of the invention can be amine or ammonium containing aliphatic polymers. By aliphatic amine polymers, it is meant a polymer which is manufactured by polymerizing an aliphatic amine monomer. In a preferred embodiment, the polymers are characterized by one or more monomeric units of Formula I: 
and salts thereof, where n is a positive integer and x is 0 or an integer between 1 and about 4, preferably 1. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent.
The invention provides an effective treatment for removing oxalate from a patient (and thereby reducing the patient""s urinary output of oxalate and urinary calculi).
The invention also provides for the use of the polymers described herein for the manufacture of a medicament for the treatment of urinary calculi, for oxalate binding or reduction of oxalate levels.
Other features and advantages will be apparent from the following description of the preferred embodiments thereof and from the claims.
As described above, the polymers employed in the invention comprise water-insoluble, non-absorbable, optionally cross-linked polyamines. Preferred polymers are polyallylamine, polyvinylamine and polydiallylamine polymers. The polymers can be homopolymers or copolymers, as discussed below, and can be substituted or unsubstituted. These and other polymers which can be used in the claimed invention have been reported in the patent literature in, for example, U.S. Pat. Nos. 5,487,888, 5,496,545, 5,607,669, 5,618,530, 5,624,963, 5,667,775, 5,679,717, 5,703,188, 5,702,696 and 5,693,675. Copending U.S. application Ser. Nos. 08/659,264, 08/823,699, 08/835,857, 08/470,940, 08/826,197, 08/777,408, 08/927,247, 08/964,498 and 08/964,536, the entire contents of which are incorporated herein by reference.
The polymer can be a homopolymer or a copolymer of one or more amine-containing monomers or a copolymer of one or more amine-containing monomers in combination with one or more non-amine containing monomers. Where copolymers are manufactured with the monomer of the above Formula I, the comonomers are preferably inert, non-toxic and/or possess oxalate binding properties. Examples of suitable non-amine-containing monomers include vinylalcohol, acrylic acid, acrylamide, and vinylformamide. Examples of amine containing monomers preferably include monomers having the Formula 1 above. Preferably, the monomers are aliphatic. Most preferably, the polymer is a homopolymer, such as a homopolyallylamine, homopolyvinylamine or homopolydiallylamine.
Other preferred polymers include polymers characterized by one or more repeat units set forth below 
or copolymers thereof, wherein n is a positive integer, y and z are both integers of one or more (e.g., between about one and about 10) and each R, R1, R2, R3 and R4, independently, is H or a substituted or unsubstituted alkyl group (e.g., having between 1 and 25 or between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino or poly(ethylamino)) or aryl (e.g., phenyl) group, and each Xxe2x88x92is an exchangeable negatively charged counterion.
In one preferred polymer, at least one of R, R1, R2, R3 or R4 groups is a hydrogen atom. In a more preferred embodiment, each of these groups are hydrogen.
In each case, the R groups can carry one or more substituents. Suitable substituents include therapeutic cationic groups, e.g., quaternary ammonium groups, or amine groups, e.g., primary, secondary or tertiary alkyl or aryl amines. Examples of other suitable substituents include hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanadine, urea, poly(alkyleneimine), such as (polyethyleneimine) and carboxylic acid esters, for example.
Preferably, the polymer is rendered water-insoluble by crosslinking. The cross-linking agent can be characterized by functional groups which react with the amino group of the monomer. Alternatively, the crosslinking group can be characterized by two ore more vinyl groups which undergo free radical polymerization with the amine monomer.
Examples of suitable crosslinking agents include diacrylates and dimethylacrylates (e.g. ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate, polyethyleneglycol dimethacrylate and polyethyleneglycol diacrylate), methylene bisacrylamide, methylene bismethacrylamide, ethylene bisacrylamide, ethylene bismethacrylamide, ethylidene bisacrylamide, divinylbenzene, bisphenol A, dimethacrylate and bisphenol A diacrylate. The crosslinking agent can also include acryloyl chloride, epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, succinyl dichloride, the diglycidal ether of bisphenol A, pyromellitic dianhydride, toluene diisocyanate, ethylene diamine and dimethyl succinate.
A preferred crosslinking agent is epichlorohydrin because of its high availability and low cost. Epichlorohydrin is also advantageous because of its low molecular weight and hydrophilic nature, increasing the water-swellability and gel properties of the polyamine.
The level of crosslinking makes the polymers insoluble and substantially resistant to absorption and degradation, thereby limiting the activity of the polymer to the gastrointestinal tract. Thus, the compositions are non-systemic in their activity and will lead to reduced side-effects in the patient. Typically, the cross-linking agent is present in an amount from about 0.5-35% or about 0.5-25% (such as from about 2.5-20% or about 1-10%) by weight, based upon total weight of monomer plus crosslinking agent. The polymers can also be further derivatized, such as alkylated amine polymers, as described, for example, in U.S. Pat. Nos. 5,679,717, 5,607,669 and 5,618,530, which are incorporated herein by reference. Preferred alkylating agents include hydrophobic groups (such as aliphatic hydrophobic groups) and/or quaternary ammonium- or amine-substituted alkyl groups.
Non-cross-linked and cross-linked polyallylamine and polyvinylamine are generally known in the art and are commercially available. Methods for the manufacture of polyallylamine and polyvinylamine, and cross-linked derivatives thereof, are described in the above U.S. Patents, the teachings of which are incorporated entirely by reference. Harada et al. (U.S. Pat. Nos. 4,605,701 and 4,528,347, which are incorporated herein by reference in their entirety) also describe methods of manufacturing polyallylamine and cross-linked polyallylamine.
As described above the polymer can be administered in the form of a salt. By xe2x80x9csaltxe2x80x9d it is meant that the nitrogen group in the repeat unit is protonated to create a positively charged nitrogen atom associated with a negatively charged counterion.
The anionic counterions can be selected to minimize adverse effects on the patient, as is more particularly described below. Examples of suitable counterions include organic ions, inorganic ions, or a combination thereof, such as halides (Clxe2x80x94 and Brxe2x80x94) CH3OSO3xe2x80x94, HSO4xe2x80x94, SO42xe2x80x94, HCO3xe2x80x94, CO3xe2x80x94, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, dihydrogen citrate, tartrate, taurocholate, glycocholate, cholate, hydrogen citrate, maleate, benzoate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. The counterions can be the same as, or different from, each other. For example, the polymer can contain two different types of counterions.
The polymers according to the invention can be administered orally to a patient in a dosage of about 1 mg/kg/day to about 1 g/kg/day, preferably between about 10 mg/kg/day to about 200 mg/kg/day; the particular dosage will depend on the individual patient (e.g., the patient""s weight and the extent of oxalate removal required). The polymer can be administrated either in hydrated or dehydrated form, and can be flavored or added to a food or drink, if desired to enhance patient acceptability. Additional ingredients such as other oxalate reducers or binders (including calcium), ingredients for treating other related indications, or inert ingredients, such as artificial coloring agents can be added as well.
For example, an enzyme which can reduce oxalate levels can be coadministered with the polymer. Suitable enzymes include oxalate decarboxylase, oxalate oxidase and additional enzymes that can function collaterally and, for example, convert products of the enzymatic reaction to harmless products. For example, peroxidase can be administered to convert hydrogen peroxide produced by oxalate oxidase.
The additional active ingredients, such as enzymes, can be administered simultaneously or sequentially with the oxalate binding polymer. Where the ingredients are administered simultaneously, the enzyme can optionally be bound to the polymer, for example, by covalent bonding or physically encapsulating the enzyme, on the exterior or interior of the polymeric particle. Covalent bonding can be accomplished by reacting the polymer and enzyme(s) with a suitable crosslinking agent. For example, polyallylamine and an enzyme can be cross-linked with epichlorohydrin, polyacrylamide and an enzyme can be cross-linked with methylenebisacrylamide and poly-2-acrylamido-2-methylpropane sulfonic acid (and its salts) and an enzyme can be cross-linked with methylenebisacrylamide.
Examples of suitable forms for administration (preferably oral administration) include pills, tablets, capsules, and powders (e.g., for sprinkling on food or incorporating into a drink). The pill, tablet, capsule, or powder can be coated with a substance capable of protecting the composition from disintegration in the esophagus but will allow disintegration as the composition in the stomach and mixing with food to pass into the patient""s small intestine. The polymer can be administered alone or in combination with a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.
The polymers of the invention can be used to treat patients, preferably humans, with high urinary or serum oxalate levels or hyperoxaluria or who are at risk of high urinary or serum oxalate levels or hyperoxaluria. For example, patients who can be treated by the administration of the polymers described herein include those who have or have had urinary calculi or kidney stones, those who have renal deficiency due to elevated oxalate levels, those who are on diets containing large amounts of oxalate, those who have ileal disease, ileal resection or jejeunoileal bypass, those who have biliary or pancreatic disease and those with a family history of calculi. Additionally, patients with cardiomyopathy, cardiac conductance disorders, cystic fibrosis, Crohn""s disease, renal failure, vulvodynia and depleted colonies of intestinal Oxalobacter formigenes.